Throughout this application various publications are referenced by arabic numerals within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms which normally govern proliferation and differentiation. For many years there have been two principal strategies for chemotherapeutic treatment of cancer: a) blocking hormone-dependent tumor cell proliferation by interference with the production or peripheral action of sex hormones; and b) killing cancer cells directly by exposing them to cytotoxic substances, which injure both neoplastic and normal cell populations. Relatively recently, cancer therapy is also being attempted by the induction of terminal differentiation of the neoplastic cells (10). In cell culture models differentiation has been reported by exposure of cells to a variety of stimuli, including: cyclic AMP and retinoic acid (1,2), aclarubicin and other anthracyclines (3), and polar planar compounds, of which the most extensively studied is hexamethylene bisacetamide (HMBA) (4-5, 9).
HMBA is capable of inducing phenotypic changes consistent with differentiation in a broad variety of cell lines (6). The characteristics of the drug-induced effect have been most extensively studied in the Friend murine erythroleukemia cell system (MELC) (6-9). MELC induction of differentiation is both time and concentration dependent. The minimum concentration required to demonstrate an effect in vitro in most strains is 2 to 3 mM; the minimum duration of continuous exposure generally required to induce differentiation in a substantial portion (&gt;20%) of the population without continuing drug exposure is about 36 hours.
The present invention provides new chemical inducers which are 2-5 times more active then HMBA. It has unexpectedly been found that compounds having two or more nonpolar components connected by a polar group and having polar groups on the termini of the compound are effective inducers of terminal differentiation. For instance, bis-hexamethylene triacetamide, which comprises three acetamide groups connected by two six-carbon chains, has been found to be a potent inducer of terminal differentiation in MELC.
This new class of compounds of the present invention may be useful for selectively inducing terminal differentiation of neoplastic cells and therefore aid in treatment of tumors in patients.